A randomised trial to assess whether the addition of a beta blocker infusion (landiolol) to standard treatment in patients with septic shock, requiring prolonged (>24 hours) support with high-dose vasopressor agents, improves organ failure (the STRESS-L trial)
| ISRCTN | ISRCTN12600919 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12600919 |
| EudraCT/CTIS number | 2017-001785-14 |
| IRAS number | 213669 |
| Secondary identifying numbers | CPMS 35229 |
- Submission date
- 04/12/2017
- Registration date
- 18/12/2017
- Last edited
- 29/01/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
Septic shock (blood poisoning) is a life-threatening condition caused by severe infection. For reasons still poorly understood, in some patients, their immune system remains excessively activated. Instead of fighting the infection, an ongoing inflammatory state results in widespread injury and failure of normal functioning of the body’s vital organs, such as the lungs, heart, brain and kidneys. A hallmark of septic shock is a very low blood pressure that does not improve with an intravenous fluid drip. Despite huge research efforts over the last 20-30 years the survival rate has remained stubbornly unchanged. Outcomes have improved for sepsis in general through earlier recognition and intervention with antibiotics, however once septic shock takes hold, the risk of dying remains very high. This research project wants to see if infusing a very short-acting beta-blocker in addition to standard treatment improves organ failure in patients with septic shock. Beta-blockers are widely used to counteract the stressful long-term actions of the hormones adrenaline and noradrenaline, for example in high blood pressure, chronic heart failure, abnormally fast heart rates and cardiac rhythms, and tremor. Recently, an Italian group gave a beta-blocker to reduce, and then maintain, heart rates of patients with septic shock at between 80-95 beats per minute. They found this treatment strategy to be safe and associated with improvements in survival and reduced time in intensive care. However, their study was relatively small and recruitment occurred at a single centre so did not provide enough information to make the use of beta-blockers a mainstream recommendation. This trial aims to repeat the Rome study in approximately 35 ICUs in the UK to see if the safety and benefits that were seen can be confirmed and will also investigate the way in which beta blockers act in septic shock patients.
Who can participate?
Adults aged 18 and older who are have septic shock.
What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive the usual care. Those in the second group receive the usual care with the addition of landiolol. For participants in the landiolol group, the rate of the drug is adjusted until their heart rate is controlled at 80-95 beats per minute and the infusion is stopped when they are able to control their heart rate themselves. Landiolol is given intravenously (IV) as an infusion whilst a participant’s heart rate is too high. This drug may be used for up to 2 weeks within the ICU where the treating team are able to monitor the participant closely. After discharge from ICU, or if the heart rate remains high after 14 days, ongoing treatment will be the decision of the treating doctor. One of the aims of this study is to better understand the biological mechanisms that are altered by beta-blockade in septic shock. As part of standard clinical care blood will be taken from a cannula (a thin tube inserted into a vein or body cavity to administer medication). Additional blood samples will be taken at study entry, on days 0, 1, 2, 4 and 6 and at the end of noradrenaline treatment (if not a sampling day). Routinely collected clinical data will be recorded for the trial. However the progress of participants will be followed at day 28 and day 90 after trial entry, at these time points the local research team will call the participant and their GP to find out how they are. The trial will not follow participants beyond 90 days.
What are the possible benefits and risks of participating?
As landiolol is an exceptionally short-acting drug, switching off the infusion is expected to reverse any possible side effects. Beta blockers are not confirmed to be useful in septic shock and it is possible that landiolol has the potential for toxicity. Full information on the possible side effects are available on request from local treating teams. The main risks are the heart could go too slowly or blood pressure could lower if a participant is sensitive to the drug. Trial participants will be closely monitored within the ICU and should they experience any side effects from the study drug, the hospital staff will take measures to stop the infusion as with any other inpatient treatment.
Where is the study run from?
This study is being run by Warwick Clinical Trials Unit (University of Warwick) and takes place in hospitals in the UK.
When is the study starting and how long is it expected to run for?
June 2017 to October 2023.
Who is funding the study?
National Institute for Health Research (UK)
Who is the main contact?
STRESS-L@warwick.ac.uk
Contact information
Scientific
Warwick Clinical Trials Unit
The University of Warwick
Gibbet Hill Road
Coventry
CV4 7AL
United Kingdom
| Phone | +44 (0)2476572905 |
|---|---|
| STRESS-L@warwick.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet STRESS-L@warwick.ac.uk |
| Scientific title | STudy into the REversal of Septic Shock with Landiolol (Beta Blockade) |
| Study acronym | STRESS-L |
| Study hypothesis | A reduction in heart rate using landiolol infusion in patients with septic shock and tachycardia improves organ failure during the 14 days after the patient is started in the trial. This study is investigate whether the changes are through a reduction in cardiac and immune dysfunction. |
| Ethics approval(s) |
Approved 09/11/2017, East of England – Essex Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, United Kingdom; +44 207 104 8107; NRESCommittee.EastofEngland-Essex@nhs.net), ref: 17/EE/0368 |
| Condition | Septic shock |
| Intervention | Current interventions as of 28/02/2019: Participants are randomised to receive standard treatment with the addition of a beta blocker infusion (landiolol) or standard treatment alone. For those in the landiolol group, the rate of drug are adjusted until the heart rate is controlled between 80-94 beats per minute. Landiolol may be used for up to 14 days within the ICU. Follow up continues for up to 90 days following randomisation. One of the aims of this study is to better understand the biological mechanisms that are altered by beta-blockade in septic shock. As part of standard clinical care blood will be taken from a cannula (a thin tube inserted into a vein or body cavity to administer medication). Additional blood samples will be taken at study entry, on days 0, 1, 2, 4 and 6 and at the end of noradrenaline treatment (if not a sampling day). These samples will be sent to University of Birmingham and University Hospitals Birmingham NHS Foundation Trust and will be used in laboratory research to help define the mechanisms involved in treating sepsis with beta blockade. These samples will be destroyed once analysis has been completed. Routinely collected clinical data will be recorded for the trial. However the progress of participants will be followed at day 28 and day 90 after trial entry, at these time points the local research team will call the participant and their GP to find out how they are. The trial will not follow participants beyond 90 days. Previous interventions: Participants are randomised to receive standard treatment with the addition of a beta blocker infusion (landiolol) or standard treatment alone. For those in the landiolol group, the rate of drug are adjusted until the heart rate is controlled between 80-94 beats per minute. Landiolol may be used for up to 14 days within the ICU. Follow up continues for up to 90 days following randomisation. One of the aims of this study is to better understand the biological mechanisms that are altered by beta-blockade in septic shock. As part of standard clinical care blood will be taken from a cannula (a thin tube inserted into a vein or body cavity to administer medication). Additional blood samples will be taken at study entry, on days 1, 2, 4 and 6 and at the end of noradrenaline treatment (if not a sampling day). These samples will be sent to University Hospitals Birmingham NHS Foundation Trust and will be used in laboratory research to help define the mechanisms involved in treating sepsis with beta blockade. These samples will be destroyed once analysis has been completed. Routinely collected clinical data will be recorded for the trial. However the progress of participants will be followed at day 28 and day 90 after trial entry, at these time points the local research team will call the participant and their GP to find out how they are. The trial will not follow participants beyond 90 days. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Landiolol |
| Primary outcome measure | Organ failure is measured using the mean SOFA score over the first 14 days from entry to the trial and whilst in ICU. Measurement of the SOFA score will cease if the patient dies or is discharged from the ICU. |
| Secondary outcome measures | Current secondary outcome measures as of 12/11/2019: 1. Mortality is measured using patient records and telephone visits at day 28 and day 90 2. Length of ICU and hospital stay are measured using patient notes up to 90 days 3. Reduction in dose and duration of vasopressor treatment is measured using patient notes for up to 14 days following randomisation Exploratory Outcome Measures: 4. Myocardial dysfunction and inflammation are measured using assays on blood samples taken on days 0, 1, 2, 4, 6 and the End of Noradrenaline Treatment Visit Previous secondary outcome measures: 1. Mortality is measured using patient records and telephone visits at day 28 and day 90 2. Length of ICU and hospital stay are measured using patient notes up to 90 days 3. Individual organ failure-days in 28 day survivors is measured using medical tests (recording SOFA score parameters - oxygenation, renal, hepatic and coagulation function) at day 28 4. Reduction in dose and duration of vasopressor treatment (total doses of adrenaline, dobutamine, phosphodiesterase inhibitors) is measured using patient notes for up to 14 days following randomisation 5. Cardiovascular safety outcomes are measured using hospital notes for the first 14 days Exploratory Outcome Measures: 6. Myocardial dysfunction and inflammation are measured using assays on blood samples taken on days 0, 1, 2, 4, 6 and the End of Noradrenaline Treatment Visit |
| Overall study start date | 01/06/2017 |
| Overall study end date | 05/10/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 340; UK Sample Size: 340 |
| Participant inclusion criteria | Current inclusion criteria as of 14/08/2020: 1. Aged 18 years or above 2. Being treated on an ICU 3. Septic shock according to internationally accepted definitions* 4. Heart rate ≥95 bpm ( at the time of randomisation) 5. Receiving vasopressor support to maintain a target blood pressure for ≥24 hours 6. Are being treated with noradrenaline at a rate ≥ 0.1 mcg/kg/min *Sepsis -3 definitions: 1. Confirmed or suspected infection requiring antibiotic therapy 2. New organ dysfunction, as evidenced by an increase in SOFA score ≥2 3. A blood lactate >2 mmol/l at any point during shock resuscitation 4. Vasopressor therapy to maintain mean arterial pressure (MAP) ≥65 mmHg In particular the presence of a blood lactate > 2 mmol/l is only necessary for the diagnosis of septic shock and is NOT necessary for randomisation 24 hours later. Previous inclusion criteria from 28/02/2019 to 14/08/2020: 1. Male or female aged 18 years or above 2. Being treated on an ICU 3. Septic shock according to internationally accepted definitions* 4. Heart rate ≥95 bpm (24 hours after start of vasopressor therapy) 5. Receiving vasopressor support to maintain a target blood pressure for ≥24 hours 6. Are being treated with noradrenaline at a rate ≥ 0.1 mcg/kg/min *Sepsis -3 definitions: 1. Confirmed or suspected infection requiring antibiotic therapy 2. New organ dysfunction, as evidenced by an increase in SOFA score ≥2 3. A blood lactate >2 mmol/l at any point during shock resuscitation 4. Vasopressor therapy to maintain mean arterial pressure (MAP) ≥65 mmHg In particular the presence of a blood lactate > 2 mmol/l is only necessary for the diagnosis of septic shock and is NOT necessary for randomisation 24 hours later. Previous inclusion criteria: 1. Male or female aged 18 years or above 2. Being treated on an ICU 3. Septic shock according to internationally accepted definitions* 4. Heart rate ≥95 bpm (24 hours after start of vasopressor therapy) 5. Receiving vasopressor support with noradrenaline to maintain a target blood pressure for ≥24 hours 6. Are being treated with noradrenaline at a rate ≥ 0.1 mcg/kg/min *Sepsis -3 definitions: 1. Confirmed or suspected infection requiring antibiotic therapy 2. New organ dysfunction, as evidenced by an increase in SOFA score ≥2 3. A blood lactate >2 mmol/l at any point during shock resuscitation 4. Vasopressor therapy to maintain mean arterial pressure (MAP) ≥65 mmHg In particular the presence of a blood lactate > 2 mmol/l is only necessary for the diagnosis of septic shock and is NOT necessary for randomisation 24 hours later |
| Participant exclusion criteria | Current exclusion criteria as of 14/08/2020: 1. Tachycardia as a result of pain, discomfort from medical devices (including endotracheal tubes), during interventions or other patient distress 2. Any form of vasodilatory shock that is not caused by sepsis 3. Noradrenaline infusion <0.1mcg/kg/min 4. >72 hours after start of vasopressor therapy 5. <12 hours since noradrenaline to treat a medical condition after than septic shock stopped 6. Having pre-existing severe cardiac dysfunction (NYHA grade 4 or more) 7. Having pre-existing severe pulmonary hypertension (mean PA pressures > 55mmHg) 8. Acute severe bronchospasm (due to asthma or COPD) 9. Untreated second or third-degree heart block 10. Untreated phaeochromocytoma 11. Prinzmetal's angina 12. A past history of ischaemic stroke or transient ischaemic attack (TIA) or untreated severe carotid stenosis. 13. Advanced liver disease with Child-Pugh Score of ≥B. 14. Known sensitivity to beta-blockers 15. Patient/legal representative unwilling to provide written informed consent 16. Known to be pregnant 17. Terminal illness other than septic shock with a life expectancy < 28 days 18. Participants who have been administered an investigational medicinal product for another research trial in the past 30 days 19. Patients in whom the clinical team feel are about to finish their noradrenaline therapy 20. Receiving extracorporeal membrane oxygenation (ECMO) treatment Previous exclusion criteria from 12/11/2019 to 14/08/2020: 1. Any form of compensatory tachycardia 2. Any form of vasodilatory shock that is not caused by sepsis 3. Noradrenaline infusion <0.1mcg/kg/min 4. >72 hours in the current cause of septic shock after start of vasopressor therapy 5. Having pre-existing severe cardiac dysfunction (NYHA grade 4 or more) 6. Having pre-existing severe pulmonary hypertension (mean PA pressures > 55mmHg) 7. Acute severe bronchospasm (due to asthma or COPD) 8. Untreated second or third degree heart block 9. Untreated phaeochromocytoma 10. Prinzmetal's angina 11. A past history of ischaemic stroke or transient ischaemic attack (TIA) or untreated 12. Severe carotid stenosis. 13. Advanced liver disease with Child-Pugh Score of ≥B. 14. Known sensitivity to beta-blockers 15. Patient/legal representative unwilling to provide written informed consent 16. Known to be pregnant 17. Terminal illness other than septic shock with a life expectancy < 28 days 18. Participants who have been administered an investigational medicinal product for 19. Another research trial in the past 30 days 20. Patients in whom the clinical team feel are about to finish their noradrenaline 21. Therapy 22. Decision of withdrawal of care is in place or imminently anticipated Previous exclusion criteria as of 28/02/2019: 1. Noradrenaline infusion < 0.1mcg/kg/min 2. > 72 hours after start of vasopressor therapy 3. Having pre-existing severe cardiac dysfunction (NYHA grade 4 or more) 4. Having pre-existing severe pulmonary hypertension (mean PA pressures > 55mmHg) 5. Acute severe bronchospasm (due to asthma or COPD) 6. Untreated second or third degree heart block 7. Untreated phaeochromocytoma 8. Prinzmetal's angina 9. A past history of ischaemic stroke or transient ischaemic attack (TIA) or untreated severe carotid stenosis. 10. Advanced liver disease with Child-Pugh Score of ≥B 11. Having been treated with any beta-blocker drug in the seventy two hours prior to screening. 12. Known sensitivity to beta-blockers 13. Patient/legal representative unwilling to provide written informed consent 14. Known to be pregnant 15. Terminal illness other than septic shock with a life expectancy < 28 days 16. Participants who have been administered an investigational medicinal product for another research trial in the past 30 days. 17. Patients in whom the clinical team feel are about to finish their noradrenaline therapy Previous exclusion criteria: 1. Noradrenaline infusion < 0.1mcg/kg/min 2. > 48 hours after start of vasopressor therapy 3. Having pre-existing severe cardiac dysfunction (NYHA grade 4 or more) 4. Having pre-existing severe pulmonary hypertension (mean PA pressures > 55mmHg) 5. Acute severe bronchospasm (due to asthma or COPD) 6. Untreated second or third degree heart block 7. Untreated pheochromocytoma 8. Prinzmetal's angina 9. A past history of ischaemic stroke or transient ischaemic attack (TIA) or untreated severe carotid stenosis. 10. Advanced liver disease 11. Having been treated with any beta-blocker drug in the seventy two hours prior to screening. 12. Known sensitivity to beta-blockers 13. Patient/legal representative unwilling to provide written informed consent 14. Known to be pregnant 15. Terminal illness other than septic shock with a life expectancy < 28 days 16. Participants who have participated in another research trial involving an investigational medicinal product in the past 30 days. 17. Patients in whom the clinical team feel are about to finish their noradrenaline therapy |
| Recruitment start date | 10/01/2018 |
| Recruitment end date | 25/09/2021 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
Study participating centres
Trust HQ, PO Box 9551
Birmingham
B15 2TH
United Kingdom
250 Euston Road
London
NW1 2PG
United Kingdom
Bordesley Green East
Birmingham
B9 5SS
United Kingdom
Grosvenor Road
Belfast
BT12 6BA
United Kingdom
Praed Street
London
W2 1NY
United Kingdom
Fulham Palace Rd
Hammersmith
London
W6 8RF
United Kingdom
Du Cane Road
London
W12 0HS
United Kingdom
Parkfield Drive
Taunton
TA1 5DA
United Kingdom
Mansfield Road
Sutton in Ashfield
NG17 4JL
United Kingdom
Upper Maudlin Street
Bristol
BS2 8HW
United Kingdom
Derby Road
Nottingham
NG7 2UH
United Kingdom
Williams Ave
Dorchester
DT1 2JY
United Kingdom
Treliske
Truro
TR1 3LJ
United Kingdom
Longfleet Road
Poole
BH15 2JB
United Kingdom
Crownhill
Plymouth
PL6 8DH
United Kingdom
Cosham
Portsmouth
PO6 3LY
United Kingdom
Westminster Bridge Rd
Lambeth
London
SE1 7EH
United Kingdom
Kayll Rd
Sunderland
SR4 7TP
United Kingdom
Barrack Rd
Exeter
EX2 5DW
United Kingdom
Denmark Hill
Brixton
London
SE5 9RS
United Kingdom
Pond St
Hampstead
London
NW3 2QG
United Kingdom
Prescot St
Liverpool
L7 8XP
United Kingdom
68 Lurgan Rd
Portadown
Craigavon
BT63 5QQ
United Kingdom
Great George St
Leeds
LS1 3EX
United Kingdom
Russells Hall
Pensnett Rd
Dudley
DY1 2HQ
United Kingdom
Clifford Bridge Rd
Coventry
CV2 2DX
United Kingdom
Lakin Rd
Warwick
CV34 5BW
United Kingdom
Moorgate Rd
Rotherham
S60 2UD
United Kingdom
Freeman Rd
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Mandeville Rd
Aylesbury
HP21 8AL
United Kingdom
Hills Rd
Cambridge
CB2 0QQ
United Kingdom
Foresterhill Health Campus
Aberdeen
AB25 2ZN
United Kingdom
Coreys Mill Ln
Stevenage
SG1 4AB
United Kingdom
Northampton General Hospital
Cliftonville
Northampton
NN1 5BD
United Kingdom
Anlaby Rd
Hull
HU3 2JZ
United Kingdom
Barry Building
Eastern Rd
Brighton
BN2 5BE
United Kingdom
Cranmer Terrace
Tooting
London
SW17 0RE
United Kingdom
1345 Govan Rd
Glasgow
G51 4TF
United Kingdom
Queen Victoria Rd
Newcastle upon Tyne
NE1 4LP
United Kingdom
Sponsor information
Hospital/treatment centre
Trust Headquaters
Po Box 9551
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
England
United Kingdom
"ROR" |
https://ror.org/014ja3n03 |
|---|
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/10/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. The Warwick Clinical Trials Unit will publish the results of the trial on their website when these are available. https://warwick.ac.uk/fac/sci/med/research/ctu/trials/stressl/publications/ (added 14/09/2023) |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from stress-l@warwick.ac.uk |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 16/02/2021 | 12/05/2021 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 25/10/2023 | 26/10/2023 | Yes | No | |
| Other publications | Pre-planned sub-study of the effect of landiolol on inflammatory and metabolomic markers | 22/01/2025 | 29/01/2025 | Yes | No |
Editorial Notes
29/01/2025: Publication reference added.
26/10/2023: The following changes were made to the trial record:
1. Publication reference added.
2. The overall end date was changed from 15/12/2021 to 05/10/2023.
14/09/2023: The following changes were made to the trial record:
1. The contact was changed.
2. The IRAS number was added.
3. The overall end date was changed from 30/11/2022 to 15/12/2021.
4. The recruitment end date was changed from 01/02/2022 to 25/09/2021.
5. The publication and dissemination plan was updated.
6. The participant level data sharing statement was updated.
7. The intention to publish date was changed from 31/03/2024 to 31/10/2023.
8. The plain English summary was updated to reflect these changes.
12/05/2021: Publication reference added.
11/12/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/11/2020 to 01/02/2022.
2. The overall end date was changed from 31/08/2021 to 30/11/2022.
3. The intention to publish date was changed from 31/12/2022 to 31/03/2024.
4. The plain English summary was updated to reflect these changes.
20/10/2020: IPD sharing statement added.
27/08/2020: Recruitment to this study is no longer paused.
14/08/2020: The inclusion and exclusion criteria were updated.
20/04/2020: Due to current public health guidance, recruitment for this study has been paused.
18/03/2020: The trial participating centres were added.
12/11/2019: The following changes were made to the trial record:
1. The secondary outcome measures were changed.
2. The exclusion criteria were changed.
06/11/2019: Internal review.
29/03/2019: The condition has been changed from "Specialty: Critical care, Primary sub-specialty: Critical Care; UKCRC code/ Disease: Infection/ Other infectious diseases, Inflammatory and Immune System/ Certain disorders involving the immune mechanism" to "Septic shock" following a request from the NIHR.
28/02/2019: The following changes were made:
1. The plain English summary was updated.
2. The interventions were updated.
3. The participant inclusion criteria was updated.
4. The participant exclusion criteria was updated.
5. The recruitment end date was changed from 09/01/2021 to 30/11/2020.
05/01/2018: Internal review.
